UA78742C2 - Benzothiazine and benzothiadiazine derivatives, method for preparing same and pharmaceutical composition containing thereof - Google Patents

Abstract

The invention concerns a compound of formula (I), wherein: R1 represents an aryl or heteroaryl; R2 represents hydrogen, halogen or a hydroxy; X represents oxygen or sulphur; Y represents oxygen, sulphur or NR wherein R represents hydrogen or an alkyl; A represents CR4R5 or NR4; R3 represents hydrogen, alkyl or cycloalkyl; R4 represents hydrogen or alkyl; or A represents i nitrogen and forms with adjacent -CHR3-the cycle (a) wherein m represents 1, 2, or 3, R3 represents hydrogen or halogen; their l isomers and their addition salts. Said compounds are useful as medicines, as AMPA modulators.

Description

Description of the invention

This invention relates to new derivatives of benzothiazine and benzothiadiazine, to the method of their preparation and 2 pharmaceutical compositions containing them.

To date, it is known that excitatory amino acids, especially glutamate, play a key role in the physiological processes of neuronal plasticity and in the mechanisms underlying learning and memorization. Pathophysiological studies have clearly shown that a deficiency in glutamatergic neurotransmission is closely related to the development of Alzheimer's disease. hemiemov, 1992, 16, 13-24; 70 Rgodgevs ip Mepgobioiodu, 1992, 39, 517-545).

Moreover, numerous works in recent years have demonstrated the existence of subtypes of excitatory receptors of amino acids and their functional interactions.

Among such receptors, the AMPA (o-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptor appears to be the receptor that is most involved in the phenomenon of physiological neuronal excitability and, especially, in the phenomena that are involved in the processes memorization For example, it was found that the learning process is associated with an increase in the binding of AMPA to its receptor in the hippocampus, one of the areas of the brain important for the processes of memory and cognition. Similarly, nootropic agents such as aniracetam have recently been described as positively modulating AMPA receptors of neuronal cells (Soshigpa! Meigospetivighu, 1992, 58, 1199-1204).

In the literature, compounds with the benzamide structure have been described as having the same mechanism of action and improving the memorization process (Izuparze, 1993, 15, 326-329). Compound BA 74, in particular, is the most active of the new pharmacological agents.

Finally, (description of patent EP 692 484)| discloses a benzothiadiazine derivative that has direct activity against the AMPA current, and (patent application MUO 99/42456)| describes, among others, specific C 29 benzothiadiazine derivatives as AMPA receptor modulators. Gee)

Derivatives of benzothiazine and benzothiadiazine to which the present invention refers, in addition to being new, unexpectedly reveal pharmacological activity against the AMPA current, which is clearly more preferable to the activity of compounds having similar structures described in the prior art. They are useful as AMPA modulators for the treatment or prevention of memory and cognitive disorders associated with aging, anxiety or depression syndromes, progressive neurodegenerative diseases, Alzheimer's disease

Alzheimer's disease, Pick's disease, Huntington's chorea, schizophrenia, the consequences of acute neurodegenerative diseases, the consequences of ischemia and the consequences of epilepsy. -

More specifically, this invention relates to the compounds of formula (1): where:

Ku is an aryl or heteroaryl group,

E" represents a hydrogen atom, a halogen atom or a hydroxy group, -I X represents an oxygen atom or a sulfur atom,

M represents an oxygen atom, a sulfur atom or a MK group, where K represents a hydrogen atom or a linear or co-branched (C.4-C) alkyl group, -I A represents a SEK group or MK, a group,

Ez represents a hydrogen atom, a linear or branched (C.4-C) alkyl group or a (C-C7) cycloalkyl group, e KE. represents a hydrogen atom or a linear or branched (C4-Cv)alkyl group, or

Kk» A is a nitrogen atom and, together with the adjacent -SNKz group, forms a ring where t is 1, 2 or 3, h--i

HF) K5 represents a hydrogen or halogen atom, t to their isomers and their addition salts with a pharmaceutically acceptable acid or base, it should be understood that: - the term "aryl group", as it should be understood, means an aromatic monocyclic group or a bicyclic group, in which at least one of the rings is aromatic, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C.1-C) alkyl, linear or branched (C.4-C) alkoxy, linear or branched (C4-C) perhaloalkyl, linear or branched (C4-C) perhaloalkyl, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C.--C) alkyl groups), aminosulfonyl ( optionally substituted by one or more 62 dinium or branched (C.--Cv)alkyl groups), (C.--Cv)alkylsulfonylamino or /phenyl

(optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C.4-C)alkyl, linear or branched (C.4-Ce)perhaloalkyl, hydroxy or linear or branched (C.i -C) alkoxy), - the term "heteroaryl group" means an aromatic monocyclic or bicyclic group in which at least one of the rings is aromatic, containing one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur, provided necessarily substituted by one or more identical or different groups selected from halogen, linear or branched (C.4-Cv)alkyl, linear or branched (C.-Cv)alkyl, linear or branched (C.4-Cv)perhaloalkyl, linear or branched (C.i-Cv)perhaloalkoxy, hydroxy, cyano, 7/0 Nitro, amino (optionally substituted by one or more linear or branched (C 1-Cb)alkyl groups), aminosulfonyl (optionally substituted by one or more linear or branched (С4-Св)alkyl groups) or (C.4-C)alkylsulfonylamino.

Pharmaceutically acceptable acids may include, without limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc.

Pharmaceutically acceptable bases may include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.

A preferred aryl group is a phenyl group.

The predominant K» group is a hydrogen atom.

A mainly represents ME; group or represents a nitrogen atom and, together with the adjacent -СМК3 group, forms a ring; where t mostly represents 1. - s o

U is mostly an oxygen atom or a sulfur atom.

The invention also relates to a method of preparing compounds of formula (1).

The method of preparation of compounds of formula (I), where A is MK; group or A is a nitrogen atom and, together with the SNK" group located near the "SNK" group, forms a ring, where t is 1, 2 or 3, which differs in that the compound of formula (I) is used as the starting material : so zo tse pe What i

IS

IS; n, " where: si c K is a linear or branched (C.4-C) alkoxy group, "K" is a hydrogen atom, a halogen atom or a linear or branched (C -C) alkoxy group, which: (a) is either subjected to reactions with an acid chloride of the formula (IP) in the presence of a base, in the environment of tetrahydrofuran or acetonitrile: -i si (1) ee) - сн СНИ - Эх - СОС -i where t is as defined for the formula (I), to obtain compounds of the formula (IM): sh» e . (M and KA ooven in sidk sn,-c 2 (F) where KK", K" and t are as defined above, which is then cyclized in a basic environment to obtain a compound of formula (M):

IN

6 o o o what

In ri 1 t b5 Kk : i.

where KU, K» and t are as defined above, which is subjected to reduction, in the medium of alcohol or dimethylformamide, in the presence of sodium borohydride, to obtain the compound of the formula (MI):

Kk, 5th century

Kk de KU, KK". and t are as defined above, which is treated with boron tribromide to give a compound of formula (MI): (M)

No o, um c where t is as defined above, o (B) or cyclized: - in the presence of an amidine of the formula (MIP): (MI) сч в-и «

We, m where K" is as defined for formula (I), to obtain the compound of formula (IX): so m. y y (xx)

KS 2 eE n shi 2 s "z where K, K" and Kz are as defined above, which: - or is reduced using a metal hydride to obtain a compound of formula (X): ш- ' со

In o x i. ' and h c iz in E,

Ko) where K, K and Kz are as defined above, - or alkylated by the action of a strong base in the presence of an alkylating agent K'AX, where K'; represents a linear or branched (C.4-C) alkyl group and X represents a halogen atom, and then o is reduced to obtain the compound of formula (XII): ko EE (xx) 1 1 1

IA and, . in b5 where KU, K", Ez and K'; are as defined above, or - in the presence of an aldehyde of the formula (XII):

what) and

IN; eat

H where K" is as defined for the formula (I), to obtain the compound of the formula (X) described above, the KU group and the Ko group, when it is a linear or branched (C 4-C ) alkoxy group, the compound of which 7 /0 of formulas (X) or (XI) are converted into hydroxy groups to obtain compounds of the formula (XIII): by (xi 1

Ho de Ko, Kz and K. are as defined for the formula (I), where the compound of the formula (MII) or (XIII) is subjected to the reaction - with the compound of the formula (XiMa) o (XiMa) vrtun-es sch x o) where Ku, X are as defined for formula (I), and U represents an oxygen atom, a sulfur atom, or a MK group, where K' represents a linear or branched (C.C.-C.V.)alkyl group, with zo - or with a compound formulas (KHIMB) « you -mesSyakh t- . c where K. and X are as defined for formula (I), for obtaining compounds of formula (1/a.) or (I/ag), specific variants of compounds of formula (1): fig)

X « shi s v Y z K, 15 where X, U, Ku, Ko, Kz and K. are as defined for formula (1), yiv. vrtu-o, 8r, (ag) (ee) x -I -o» in;

Co) where X, U, Ku, Co and t are as defined for formula (1), where compounds of formulas (1/a.) and (I/a"): if necessary, purified according to conventional techniques purification, optionally separated into their (F) isomers according to conventional separation techniques and converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base.

The method of preparation of compounds of the formula (I), where A represents the SK AK" group, which differs in that the compound of the formula (XM) is used as the starting material: b5

1 (XU)

Kk and shchi

IS

In 1 o where:

K is a linear or branched (C.4-C) alkoxy group,

K" represents a hydrogen atom, a halogen atom or a linear or branched (C -C) alkoxy group, which is subjected to the action of chloroacetone in the presence of a mineral base in the medium of dimethylformamide to obtain a compound of the formula (ХМИ): , (ХМ) ке, БО

Gi v. in 1 o a where Ki K" are as defined above, which is subjected to rearrangement in the basic environment to obtain a compound of the formula (CHMI):

E (XM) Ge)

Vrach and Vo, kE s zo 1 "no Z brch-de Ki K" are as defined above, which is deacetylated by heating in a reflux condenser in a benzene environment in the presence of d) c5 excess ethylene glycol and a catalytic amount of p-toluenesulfonic acid for obtaining a compound of the formula ych- (HMII): 1 - (HM)

Kk, « - s '. Kk 2 mch y h/ , - where Ki K" are as defined above, which are subjected to hydrolysis in an acid medium to obtain a compound of the formula (xXixXa): (ee)

HiHa -1 t (HiHa) and o, sh»

Co)'

Kk 7 a

HF) where Ki K" are as defined above, whose nitrogen atom is optional, when K z is other than a hydrogen atom, is protected by a protecting group and which is then, after treatment with a strong base, treated with a compound of the formula K'5- P, where K'z is a linear or branched (C 1-C) alkyl group or (C 3-SU)cycloalkyl group and P is a leaving group, to obtain, after deprotection of the nitrogen atom, the compound of the formula (XIX'a ) b5

' (XIX)

Ek, 50, .

KE 2 o where KU, K" and Kz are as defined above, where the compound of the formula (XixXa) or (XIX'a), represented by the formula (XIX): its (their 5O,

U those Kk, o where Ki K» have the same values, and Kz is as defined for formula (1): - or subject to catalytic reduction to obtain the compound of formula (XX): (хх) ' n (8) ку Kk, where Ki K" are as defined above, Ge or converted into an alcohol by the action of a hydride, the hydroxy group of which is converted into a halogen atom by the action of a suitable reagent to obtain a compound of the formula (XXI): M cha t (XXI)

In 1 f s m. i

I'm from

Kk, "where Ki K" are as defined above, and K'5 represents a halogen atom, not) c - or subjected to the action of the organomagnesium compound KAMoVg, where Ku; represents a linear or branched c" (C4-C) alkyl group, to obtain a compound of the formula (ХХБ): т (ХХБ) " -I (ee) vk - u la iz 50 where KU, K" and K; are as defined above, where the compound of formula (XIX)

IR) - or subjected to catalytic reduction to obtain a compound of the formula (XXI):

In (XXI) 1 !

F) name) Kk Kk, because Kk 4 where K, K» and K; are as defined above, - or its hydroxy group is converted into a halogen atom by the action of a suitable reagent to obtain a compound of the formula (XXII): b5

I: (XXI) and 50, h "

Kk v i, 4 I.

EE. where K, K» and K; are as defined above, and K'5 represents a halogen atom, the K' group and the K0 group, when it 70 represents a linear or branched (C 4 -Cb)alkyl group, the compounds of formulas (XX)-(XXII) which are converted in the hydroxy group to obtain the compound of the formula (XXIM): no. (xxM)

And KOH

2o Kv, where Ko, K, and K5 are as defined for the formula (I), where the compound of the formula (XXIM) is subjected to the reaction - with the compound of the formula (XiMa) (XMa) with sovi ki or V o x where Ku, X are as defined for formula (I), and M" represents an oxygen atom, a sulfur atom or an ME" group, c where K! is a linear or branched (C1-C) alkyl group, or with a compound of the formula

Zo de Ki. and X are as defined for formula (1), c. to obtain the compound of the formula (1/5), a specific variant of the compound of the formula (1):

MN in s hu B; in p where X, XU, K., Ko, Kz, Ku, Kv are as defined for formula (I), which is purified, if necessary, according to -I to the usual purification technique, optionally separated into its isomers according by conventional separation techniques and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base. -I The invention also relates to pharmaceutical compositions that contain, as an active ingredient, a compound of formula (I) with one or more appropriate inert, non-toxic excipients. Among the pharmaceutical compositions according to this invention can be mentioned more specifically those that are acceptable for oral,

Kk" of parenteral (intravenous or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, cakes, suppositories, creams, ointments, dermal gels, injected preparations, drinkable suspensions, etc.

Acceptable dosage may vary depending on the nature and complexity of the disease, route of administration, age and weight of the patient. The dosage ranges from 1 to 500 mg per day in one or more administrations. The following examples demonstrate the present invention and are not intended to limit its scope in any way.

Products that are known or manufactured according to well-known methods of preparation are used as raw materials.

The structures of the compounds described in the Examples were determined according to conventional spectrophotometric techniques (infrared radiation, NMR, mass spectrometry...).

Example 1: 5,5-Dioxido-2,3,3Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,41-benzothiadiazin-7-yl phenyl carbonate

Step A: M-(2--(Aminosulfonyl)-4-methoxyphenyl-4-chlorobutanamide 65 144 mmol of triethylamine and then, dropwise, a solution containing 135 mmol of 4-chlorobutanoic acid chloride in 30 ml of tetrahydrofuran (THF) is added to a solution containing 96b4mmol

of 2-amino-5-methoxybenzenesulfonamide in 200 ml of THF. After stirring overnight at ambient temperature, the THF was evaporated and the residue was added to water. After extraction with ethyl acetate, the organic phase is washed and dried. After evaporation, the expected product is obtained in the form of oil.

Stage B: 5,5-Dioxo-7-methoxy-2,3-dihydro-1H-pyrrolo|2,1-c|(1,2,41-benzothiadiazine

The product obtained at the previous stage is stirred overnight at ambient temperature in 320 ml of an aqueous 1M solution of sodium hydroxide. After adding 5 Oml of ethyl acetate and vigorous stirring, the expected product that has precipitated is filtered off, washed and dried.

Stage C: 5,5-Dioxido-7-methoxy-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(/1,2,41benzothiadiazine 70 106.5 mmol of sodium borohydride is added to the suspension, which containing 335.5 mmol of the product obtained in the previous step in 40 mL of dimethylformamide (DMF). After stirring overnight at ambient temperature, the reaction mixture was cooled and then 7500 mL of ice-cold 1 M hydrochloric acid was added to the above mixture. The expected product precipitated and was filtered off. .

Melting point: 193-19820

Stage 0: 5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|-benzothiadiazin-7-ol 79.3mmol of boron tribromide is added dropwise to the suspension , which contains 26.7 mmol of the product obtained in the previous step, in ZbOml of dichloromethane, which is maintained at -602C under nitrogen. The temperature is maintained for one hour and then everything is returned to ambient temperature and stirred overnight. After cooling the reaction mixture in an ice bath 100 mL of water is added and the biphasic system formed is vigorously stirred. The suspension thus formed is filtered. The resulting white solid is washed with water, ether, and dried to give the expected product.

Melting point: 237-24296

Stage E: 5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|-benzothiadiazin-7-yl phenyl carbonate Ge 0.175 ml of triethylamine, 5 mg 4 -dimethylaminopyridine and, dropwise, 0.13 bml of phenyl chloroformate dissolved in 0.2 ml of dichloromethane (CHNOCl) are added to a suspension containing 0.83 mmol of the compound described in the previous

Stages, in ZOml SNoSIiI". After stirring overnight at ambient temperature, the solution was washed with 1M hydrochloric acid and then saturated sodium chloride solution, dried and evaporated. After adding the residue to ether, the expected product is obtained by filtration. Ge

Melting point: 197-19820 «

Elemental microanalysis: part 5

Fo theoretically 56.66 4.47 7.77 8.90 so 3B Cho empirically 56.44 4.55 7.61 9.02

The following Examples were prepared according to the methodology described in Example 1 using the appropriate starting materials.

Example 2: O-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-c1(1,2,4|-benzothiadiazin-7-yl) O-phenyl « thiocarbonate The expected product is obtained by replacing phenyl chloroformate in Stage E with phenyl thiochloroformate. Melting point: 252-25420

Elemental microanalysis: -I s nm 5

Fo theoretically 54.24 4.28 7.44 17.03 bo Fo empirically 53.55 5.02 7.39 17.47

Example C: O-(5,5-Dioxido-2,3,Za,4-tetrahydro-1H-pyrrolo|2,1-si(1,2,4benzothiadiazin-7-yl)Z-phenyl t»dithiocarbonate

KZ The expected product is obtained by replacing phenyl chloroformate in Stage E with phenyl dithiochloroformate.

Melting point: 210-21426

Elemental microanalysis:

GF) snm in ko Fo theoretically 52.02 4.11 7.14 24.51

Fo empirically 51.85 4.10 7.36 24.69 60 Example 4: O-(5,5-Dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo|2,1-c1(/1, 2, Benzothiadiazin-7-yl O-(4-chlorophenyl) thiocarbonate

The expected product is obtained by replacing phenyl chloroformate in Stage E with 4-chlorophenyl thionechloroformate.

Melting point: 189-19492С bo Elemental microanalysis:

with nm in S

Fo theoretically 49.69 3.68 6.82 15.61 8.63

Fo empirically 49.39 3.64 7.02 16.20 9.70

Example 5: O-(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl O-phenyl thiocarbonate

Stage A: 7-Methoxy-4H-1,2,4-benzothiadiazine 1,1-dioxide

A suspension of 3.0 g of 2-amino-5-methoxybenzene-sulfonamide was stirred overnight at 802 °C in the presence of 1.31 g of formamidine hydrochloride and 2.27 ml of triethylamine in 50 ml of toluene. Toluene is evaporated under vacuum. The residue is added to water and the sediment is filtered.

Stage B: 7-Methoxy-4-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide 2.88 g of the product obtained in the previous Stage is added in portions to a suspension of Uml DMF, which contains 57Omg 6095 Man in mineral oil . The mixture is stirred for 30 minutes until a black solution is obtained. 929 ml of 75 iodoethane is then added dropwise. Stirring is continued for 1 hour. and the reaction mixture is precipitated by adding water. The precipitate is filtered off and washed with water and then with ether to give the expected product.

Stage C: 7-Methoxy-4-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide 1.19 g of sodium borohydride is added to a suspension of 2.37 g of the product of the previous stage in 40 ml of ethanol. The mixture gradually becomes homogeneous. After the reaction within an hour at ambient temperature, the mixture is cooled in an ice bath and neutralized by adding 1M NOSI. The white precipitate is stirred for 15 minutes. and the product specified in the header is filtered.

Stage 0: 4-Ethyl-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-ol 1,1-dioxide 79.3 mmol of boron tribromide is added dropwise to a suspension containing 2 g of the product obtained in the previous step Stages, in 200 ml of dichloromethane, which is maintained at -602C under nitrogen. The temperature is maintained cm for one hour and then everything is returned to ambient temperature and stirred (o) overnight. After cooling the reaction mixture in an ice bath, add 100 ml of water and vigorously stir the two-phase system. The suspension formed in this way is filtered. The resulting solid is washed with water, ether, and dried to give the expected product. high school

Melting point: 214-2189260

Stage E: O-(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl) O-phenyl thiocarbonate -

The expected product is obtained according to the method described in Step E of Example 1, replacing phenyl im-chloroformate with phenyl thionechloroformate.

Melting point: 173-17590 so

Elemental microanalysis: h-s nm 5

Fo theoretically 52.73 4.43 7.69 17.60

Fo empirically 52.81 4.68 7.66 17.75 « 70 Example 6; O-(4-Ethyl-1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl) 3-phenyl dithiocarbonate ns The expected product is obtained according to the method described for Example 5, substituting phenyl dithiochloroformate for the phenyl thionechloroformate in Step E.

Melting point: 228-23226

Elemental microanalysis: c nm 5 (Fe) Fo theoretically 50.50 4.24 7.36 25.28 -1 Fo empirically 50.07 4.09 7.57 25.31 i» 20 Example 7: О-(4- Ethyl 1,1-dioxido-3,4-dihydro-2H-1,2,4-benzothiadiazin-7-yl) O-(4-chlorophenyl) thiocarbonate

The expected product is obtained according to the procedure described for Example 5, substituting 4-chlorophenyl thionechloroformate for phenyl thionechloroformate in Step E.

Melting point: 155-15692C

Elemental microanalysis:

Ge) with nm in S

Fo theoretically 48.18 3.79 7.02 16.08 8.89 o Fo empirically 48.64 3.93 6.91 16.08 8.98 60 Pharmacological studies of products according to this invention

Study of excitatory currents caused by AMPA in Heporiz a oocytes - Method:

MRNYK is obtained from the cerebral cortex of male MUyviag rats by the guanidine thiocyanate/phenol/chloroform method. Poly(A") mRNA was separated by chromatography on oligo-4T cellulose and injected in bo amounts of BOng per oocyte. Oocytes were left to incubate for 2-3 days at 182 to allow receptor expression and then stored at 8-10.

Electrophysiological recording is carried out in the Riekhidiase U chamber at 20-246C in an environment of ОВ2 |). Ex. 7001., 1973, 184, 321-334) by the "voltage-clamp" method using two electrodes, with the third electrode placed in a bath that serves as a sample.

All compounds are injected through the incubation medium and the electrical current is measured at the end of the injection period.

AMPA is used in TOMM concentration. For each tested compound, determine the concentration that doubles (EC2X) or increases by five times (EC5X) the strength of the current caused by AMPA itself (from 5 to B5ONA).

B - Results:

The compounds of the present invention enhance the excitatory effects of AMPA to very significant levels and their activity is very superior compared to the compounds referred to. The compound of Example 2 is especially important

ES2OX at the level of 1.8MM and the value of ES5BX at the level of 9.6MM.

Pharmacological composition

The formula for preparing 1000 tablets, each of which contains 100 mg of the compound of Example 1 100 g hydroxypropyl cellulose 2 g wheat starch 1 g lactose 1 g magnesium stearate Zg talc Zg zv

Claims (9)

The formula of the invention of Art 1. Compounds of formula (1): S and schi zo NV ShZO- 0 y y N yy ! nya shchi k-t « Her and ; But not Kk пт - и- их: s ' where: "Ku represents an aryl or heteroaryl group, 2c E" represents a hydrogen atom, a halogen atom or a hydroxy group, X represents an oxygen atom or a sulfur atom, :z" M represents an oxygen atom , a sulfur atom or ME group, where K represents a hydrogen atom or a linear or branched (C.4-Cv)alkyl group, A represents a SK E»5 group or MEgd group, -I Ez represents a hydrogen atom, linear or branched ( C.4-C) alkyl group or (C-C7) cycloalkyl group, KE. represents a hydrogen atom or a linear or branched (C4-C8) alkyl group, or coA represents a nitrogen atom and, together with the adjacent -SNK3 group, -I forms a ring where t is 1, 2 or 3, iz m Co.). o K represents a hydrogen or halogen atom, their isomers and their addition salts with a pharmaceutically acceptable acid or base, where it should be understood that: - the term "aryl group", as it should be understood, means an aromatic monocyclic group or a bicyclic group in which at least one of the rings is aromatic, optionally substituted by one or more of the same or different groups selected from halogen, linear or branched (C 1 -C 1 )alkyl, linear or branched (C 1 -C 1 )alkyl, linear or branched (C.4-Ce)perhaloalkyl, linear or branched (C.4-C)perhaloalkyl, hydroxy, cyano, nitro, amino (optionally substituted by one or more linear or branched (C.--C)alkyl groups), aminosulfonyl ( optionally substituted by one or more 65 linear or branched (C-i-Cbv)alkyl groups), (Ci-Cv)alkylsulfonylamino or /phenyl (optionally substituted by one or more identical or different groups selected from halogen, linear or open alkylated (C.4-C)alkyl, linear or branched (C.4-Ce)perhaloalkyl, hydroxy or linear or branched (C.i-C)alkyl), - the term "heteroaryl group" means an aromatic monocyclic or bicyclic group, in which at least one of the rings is aromatic, containing one, two or three identical or different heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C .4-Cv)alkyl, linear or branched (C.-Cv)alkyl, linear or branched (C.4-Cv)perhaloalkyl, linear or branched (C.i-Cv)perhaloalkyl, hydroxy, cyano, nitro, amino ( optionally substituted by one or more linear or branched (C 4-C) alkyl 7/0 groups), aminosulfonyl (optionally substituted by one or more linear or branched (C 4-C) alkyl groups) or (C.4-C )alkylsulfonylamino. 2. Compounds of formula (I) according to claim 1, which differ in that K; is an aryl group. 3. Compounds of formula (I) according to claims 1 or 2, which differ in that Co is a hydrogen atom. 4. Compounds of formula (I) according to any of claims 1-3, which differ in that A is an MKal group. 5. Compounds of formula (I) according to any of claims 1-3, which differ in that A, together with the adjacent -SNKz group, forms a ring. - 5 M 6. Compounds of formula (I) according to claim 5, which differ in that t is 1. 7. The method of obtaining compounds of the formula (I), where A is a MK group or A is a nitrogen atom and, together with the adjacent -SNK3 group, forms a ring where t is 1, 2 or 3, which differs in that , that as a starting material - -- M s « ' - use the compound of formula (I): g o) ' (1) zb m. 1 5. c c c! MN. ! - с т :з" where: K represents a linear or branched (C.4-C) alkoxy group, K" represents a hydrogen atom, a halogen atom or a linear or branched (C -C) alkoxy group, -1 which: (а) or react with an acid chloride of the formula (IP) in the presence of a base, in an environment (ee) of tetrahydrofuran or acetonitrile: -1 СИ-СН.А(СНо)-СНо-СОСІ, (PI) where t is as defined for of the formula (I), to obtain the compound of the formula (IM): their E" (M) " o MH - sen OH NO, I ime) where: where Ki K" are as defined above, which is then cyclized in a basic medium with by obtaining compound 6o of formula (M): b5 o o o ' y y . K 2 - M is M 10 2 ' t where K", Ko and t are as defined above, which is subjected to reduction, in the medium of alcohol or dimethylformamide, in the presence of sodium borohydride, to obtain the compound of the formula (MI): . K Sho 20 Ku MN ! M Kk 2 ' s 25 t (8) where Ku, K" and t are as defined above, which is subjected to the action of boron tribromide to obtain the compound of the formula (MI): z o a (MI) with new and Z M. y - МН со и - M Kk, t ' « shi s where t is as defined above, (B) or cyclized: z -1) in the presence of amidine of the formula (MI): МН (МИ) Й -И ---I am in (ee) Sh MN. at. 1" 50 where K" is as defined for formula (I), to obtain a compound of formula (IX): in. (х) Ко) 59 ше чо Ф) МН И ' ко Кк 2 where KU, K" and Kz are as defined above, which: 60 - or reduced using a metal hydride to obtain a compound of formula (X) : b5 c. (o) o Sho N ; MI A. ' ' KE. ge where K, K and Kz are as defined above, - or alkylated by the action of a strong base in the presence of an alkylating agent КАХ, where Ku; represents a linear or branched (C 4-C) alkyl group and X represents a halogen atom, and then is reduced to obtain the compound of formula (XII): ' (XI) Кк 1 о ЗМ щ я ' ' Е и щ where К, К »2, Ez and K; are as defined above, or o -2) in the presence of an aldehyde of the formula (XII): NOT. where K" is as defined for formula (I), to obtain a compound of formula (X), described above, with compounds of formulas (X) or (XI), in which the group is K'. and the Ko group, when it is a linear or branched (С 4-Св) alkoxy group, is converted into a hydroxy group to obtain a compound of the formula (XII): on (XII) 50, « I M sh - - with in. ' - Kk, so de K»o, Kz and GE. are as defined for the formula (I), where the compound of the formula (III) or (XIII) is subjected to the reaction -I - with the compound of the formula (XiIMa) o НИ (ХИМа) т» 0 КЙ- - 71 - - Сх -- . Ds E 4 ' 22 where Ku, X are as defined for formula (I), and U represents an oxygen atom, a sulfur atom or a MK group, Ge! where K' represents a linear or branched (C, -C) alkyl group, - or with a compound of the formula (XIM) where vi-M- СХ, (ХМ) where K and X are as defined for formula (I) , 60 to obtain a compound of formula (I/a.) or (I/a"), specific variants of compounds of formula (1): b5 I/a Kk - y 7 - I ЕЯ2e Ye Ha o (Mah) She Other X Ж c. | K, Kk, where X, U, Ku, Ko, Kz and K. are as defined for formula (1), k.- x----- o v (mag) o Y shcha chn Xx t M o t ' where X, U, Ku, Ko and t are as defined for formula (1), where the compounds of formulas (I /ah) and (I/ag): if necessary, purified according to conventional purification techniques, sc optionally separated into their isomers according to conventional separation techniques and converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base. and) 8. The method of obtaining compounds of the formula (I), where A represents the SK AK»5 group, which differs in that the compound of the formula (XM) is used as a starting material: ! (HU) k ! claim 50; « mn m s ' Kk 7 ' h- where: K is a linear or branched (C.4-C) alkoxy group, "K" is a hydrogen atom, a halogen atom or a linear or branched (C - Cb) alkoxy group, which is subjected to - the action of chloroacetone in the presence of dimethylformamide to obtain a compound of the formula: 70 action i f i f (XM) c E" (XM) "» 1 5 m -I so . Y ' o -I their 20 where KU and Ko are as defined above, which is subjected to rearrangement in the basic medium with Kz to obtain a compound of the formula (ХМ): ' (ХМИЙ) Кк, я 9; | Mn F) and ime) ' eE Z ' bo no o de Ki K" are as defined above, which is de-ethylated by heating under reflux in a benzene medium in the presence of an excess of ethylene glycol and a catalytic amount of p-toluenesulfonic acid to obtain a compound of the formula ( HM): b5 ' (HMI) k, i Y | Mn! and F; oso u de Ki Ko" are as defined above, which are subjected to hydrolysis in an acid environment to obtain a compound of the formula (XiXXa): "(XIXa) Kk 1 ZO; Mn ' Kk 2 ' o where Ki K" are as defined above, the nitrogen atom of which is optionally, when K z is other than a hydrogen atom, protected by a protecting group and which is then, after treatment with a strong base, treated with a compound of the formula K 3-P, c where Kz represents a linear or branched (C 4-C) alkyl group or a (C 3-C 7 )cycloalkyl group and P is a leaving group, with the result, after deprotection of the nitrogen atom, of the compound of the formula (XIX 'a) ' (XIX a) KK is 9 units of Mn "I - E Kk, 2 's o m. where K, K" and Kz are as defined above, where the compound of the formula (XiXa) or (XIX'a ), represented by the formula (XIX): ' (XIX) « CC is | at; - with | Mn 2" : tu Kz 2 ' and o so de Ki K" have the same values, and Kz is as defined for formula (1): -I - or subjected to catalytic reduction to obtain the compound of formula (XX): ' (XX) road K. ZO; Ko) Y Mn o 7 ' ГИ where Ki K" are as defined above, - or converted into an alcohol by the action of a hydride, the hydroxy group of which is converted into a halogen atom by the action of a corresponding reagent to obtain a compound of the formula (XXI): b5 ' (XXI) KK. i | Mn in ' Z . , ' Kk ni de Ki K" are as defined above, and K'5 represents a halogen atom, - or exposed to the action of the organomagnesium compound КАМоВг, where Ku; represents a linear or branched (С4-Св)alkyl group, with the preparation of the compound of the formula (ХХБ): ' (ХХБ) Кк 1 с. 9; A lot. , k, on where KU, K» and K; are as defined above, where the compound of the formula (XXII) is subjected to catalytic reduction to obtain the compound of the formula (XXII): - (XXII) i) ! 5 9; Mn sch in « ' Z . , Kk 54 Fo 4 and - where KK, K» and K'; are as defined above, - or its hydroxy group is converted into a halogen atom by the action of a suitable reagent to obtain a compound of the formula (XXII!): "E" (XXII) 7 o, o) that | chn . i? КК, , И И со Кк 4 Кк 5 where К, К» and К; are as defined above, and К'5 represents a halogen atom, the group К' 4 and the group Ко when it Ш- represents a linear or a branched (C 1-C) alkoxy group, compounds of the formulas (XX) - (XXI) which are converted into their 20 tihydroxy groups to obtain a compound of the formula (XXIM): gz on (XXIM) ZO; Neck o B. 2 ime) in, in, 60, and - where K", K. and K5 are as defined for the formula (I), where the compound of the formula (XXIM) is subjected to the reaction - with the compound of the formula (XiIMa) b5 ХиМА кЙ-'-- 2 - 2 61679 х ' where Ku, X are as defined for formula (I), and U represents an oxygen atom, a sulfur atom or a MK group, where K' represents a linear or branched (C .-C) alkyl group, - or with a compound of the formula (KHIM) ki-M- C - X, (KHIMB) where Ki and X are as defined for the formula (I), with the preparation of a compound of the formula (1/5) , a specific version of the compound of formula (1): Iv) M --y -2.2-- (0 is n) iia | 9; МН х в сн 2 ра - а ' Кк, КОП where Х, ХУ, К., Ко, Кз, Ку, Кв are as defined for formula (I), which is purified, if necessary, according to the usual purification technique, optionally separated into its isomers, in accordance with conventional separation techniques, and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base. and) 9. A pharmaceutical composition that contains as an active ingredient a compound according to any one of claims 1-6 in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers. c zo 10. A pharmaceutical composition according to claim 9, which contains as an active ingredient a compound according to any one of claims 1-6, for use as a medicinal product, such as AMPA modulators. - shi I I I . - Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 5 04/25/2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. uh- - with . and? -I (ee) -I iz 50 Ko) F) ime) 60 b5